This invention relates to novel polymorphic forms of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridin-2-yl)ethenyl]indazole (also referred to as “Compound 1”)
that are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to compositions including such polymorphic forms, and to methods of using such compositions in the treatment of abnormal cell growth in mammals, especially humans.
Compound 1, as well as pharmaceutically acceptable salts thereof, are described in U.S. Pat. No. 6,534,524 and U.S. Pat. No. 6,531,491. Methods of making Compound 1 are described in U.S. Pat. No. 7,232,910 and U.S. Application Publication Nos. 2006-0091067 and 2007-0203196 and in WIPO International Publication No. WO 2006/048745. Polymorphic forms and pharmaceutical compositions of Compound 1 are also described in U.S. Application Publication No. 2006-0094763 and WIPO International Publication No. WO 2006/123223. Dosage forms of Compound 1 is also described in U.S. Application Publication No. 2004-0224988.
Compound 1 is a potent and selective inhibitor of vascular endothelial growth factor (VEGF)/platelet-derived growth factor (PDGF) receptor tyrosine kinase (RTK) being developed for use in early to late stage cancers. Protein tyrosine kinases have been identified as crucial targets in the therapeutic treatment of cancer. Growth factor ligands and their respective RTKs are required for tumor angiogenesis and growth. VEGF and PDGF are critical components in the process leading to the branching, extension, and survival of endothelial cells forming new blood vessels during angiogenesis. Unwanted angiogenesis is a hallmark of several diseases, such as retinopathies, psoriasis, rheumatoid arthritis, age-related macular degeneration (AMD), and cancer (including solid tumors) Folkman, Nature Med., 1, 27-31 (1995).
As understood by those skilled in the art, it is desirable to have crystalline or amorphous forms, that possess physical properties amenable to reliable formulation and manufacture. Such properties include filterability, hygroscopicity, and flow, as well as stability to heat, moisture, and light.
Polymorphs are different crystalline forms of the same compound. The term polymorph may or may not include other solid state molecular forms including hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water) of the same compound. Crystalline polymorphs typically have different crystal structures due to a different packing of the molecules in the lattice. This results in a different crystal symmetry and/or unit cell parameters which directly influences its physical properties such as the X-ray diffraction characteristics of crystals or powders.
Polymorphic forms are of interest to the pharmaceutical industry and especially to those involved in the development of suitable dosage forms. If the polymorphic form is not held constant during clinical or stability studies, the exact dosage form used or studied may not be comparable from one lot to another. It is also desirable to have processes for producing a compound with the selected polymorphic form in high purity when the compound is used in clinical studies or commercial products since impurities present may produce undesired toxicological effects. Certain polymorphic forms may also exhibit enhanced thermodynamic stability or may be more readily manufactured in high purity in large quantities, and thus are more suitable for inclusion in pharmaceutical formulations. Certain polymorphs may display other advantageous physical properties such as lack of hygroscopic tendencies, improved solubility, and enhanced rates of dissolution due to different lattice energies.
The discussion of the background to the invention herein is included to explain the context of the present invention. This is not to be taken as an admission that any of the material referred to was published, known, or part of the common general knowledge in any country as of the priority date of any of the claims.